US6509346B2ExpiredUtilityPatentIndex 92
Chemokine receptor antagonists and methods of use therefor
Est. expiryJan 21, 2018(expired)· nominal 20-yr term from priority
A61P 37/06A61P 31/18A61P 37/00A61P 9/10A61P 3/10A61P 7/00A61P 37/08A61P 43/00A61P 25/28A61P 29/00A61P 1/04A61P 19/02A61P 17/06A61P 11/06C07D 491/04C07D 211/46C07D 409/06C07D 471/04C07D 495/04C07D 313/12C07D 401/06C07D 405/06C07D 211/52A61K 31/55
92
PatentIndex Score
22
Cited by
113
References
83
Claims
Abstract
Disclosed are novel compounds and a method of treating a disease associated with aberrant leukocyte recruitment and/or activation. The method comprises administering to a subject in need an effective amount of a compound represented by:and physiologically acceptable salts thereof.
Claims
exact text as granted — not AI-modifiedWhat is claimed:
1. A method of treating a disease associated with aberrant leukocyte recruitment and/or activation mediated by chemokine receptor function, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:
or physiologically acceptable salts thereof, wherein:
n is an integer from one to four;
M is >NR 2 or >CR 1 R 2 ;
R 1 is —H, —OH, a halogen, an aliphatic group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR 3 R 4 , or R 1 is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;
R 2 is —OH, an acyl group, a substituted acyl group, —NR 5 R 6 , an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group;
R 3 , R 4 , R 5 and R 6 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or
R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;
said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl;
Z is represented by:
wherein:
X 1 is —O—, —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —O—CH 2 —, —CH 2 —O—, —NR c —CH 2 —, —CH 2 —NR c —, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NR—CO— or —CO—NR c —;
R c is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group;
R 40 is —COOH, —NO 2 , a substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR 24 R 25 , —CONR 24 R 25 , Q-(aliphatic group), Q-(substituted aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), —(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 or —(O) u —(CH 2 ) t —NHC(O)O—R 20 ;
R 20 , R 21 or R 22 are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or
R 21 and R 22 taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring;
Q is —NR 24 C(O)—, —NR 24 S(O) 2 — or —C(O)O—;
R 24 and R 25 are independently —H, —OH, an aliphatic group or a substituted aliphatic group;
u is zero or one; and
t is an integer from zero to 3.
2. The method of claim 1 wherein
R 1 is, —H or —OH; and
R 2 is an aromatic group or a substituted aromatic group.
3. The method of claim 1 wherein R 40 is —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 .
4. The method of claim 3 wherein u is zero and t is one to three.
5. The method of claim 3 wherein u is one and t is zero.
6. The method of claim 3 wherein u and t are both zero.
7. The method of claim 1 wherein R 40 is an aliphatic group that is substituted with —NR 24 R 25 or —CONR 24 R 25 .
8. The method of claim 1 wherein R 40 is —O-(aliphatic group) or —O-(substituted aliphatic group).
9. The method of claim 1 wherein R 40 is —COOH.
10. The method of claim 1 wherein X 1 is —CH 2 —O—.
11. A method of treating a disease associated with aberrant leukocyte recruitment and/or activation mediated by chemokine receptor function, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:
or a physiologically acceptable salt thereof, wherein:
M is CR 1 R 2 ;
R 1 is —OH;
R 2 is 4-chlorophenyl;
n is two;
Z is represented by:
X 1 is —CH 2 —O—; and
R 40 is
12. A compound represented by the following structural formula:
or physiologically acceptable salt thereof, wherein:
n is an integer from one to four;
M is >NR 2 or >CR 1 R 2 ;
R 1 is —H, —OH, a halogen, an aliphatic group, (aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR 3 R 4 , or R 1 is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;
R 2 is —OH, an acyl group, a substituted acyl group, —NR 5 R 6 , an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group;
R 3 , R 4 , R 5 and R 6 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or
R 1 and R 2 , R 3 and R 4 , or R 5 and R 1 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;
said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl;
Z is represented by:
wherein:
X 1 is —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —O—CH 2 —, —CH 2 —O—, —NR c —CH 2 —, —CH 2 —NR c —, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NR c —CO—, —O— or —CO—NR c —;
R c is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group;
R 40 is —COOH, —NO 2 , a substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR 24 R 25 , —CONR 24 R 25 , Q-(aliphatic group), Q-(substituted aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), —(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 or —(O) u —(CH 2 ) t —NHC(O)O—R 20 ;
R 20 , R 21 or R 22 are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or
R 21 and R 22 taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring;
Q is —NR 24 C(O)—, NR 24 S(O) 2 — or —C(O)O—;
R 24 and R 25 are independently —H, —OH, an aliphatic group or a substituted aliphatic group;
u is zero or one; and
t is an integer from zero to 3.
13. The compound of claim 12 wherein
R 1 is —H or —OH; and
R 2 is an aromatic group of substituted aromatic group.
14. The compound of claim 12 wherein R 40 is —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 .
15. The compound of claim 14 wherein u is zero and t is one to three.
16. The compound of claim 14 wherein u is one and t is zero.
17. The compound of claim 14 wherein u and t are both zero.
18. The compound of claim 12 wherein R 40 is an aliphatic group that is substituted with —NR 24 R 25 or —CONR 24 R 25 .
19. The compound of claim 12 wherein R 40 is —O-(aliphatic group) or —O-(substituted aliphatic group).
20. The compound of claim 12 wherein R 40 is —COOH.
21. The compound of claim 12 wherein X 1 is —CH 2 —O—.
22. A compound represented by the following structural formula:
or a physiologically acceptable salt thereof, wherein:
M is CR 1 R 2 ;
R 1 is —OH;
R 2 is 4-chlorophenyl;
n is two;
Z is represented by:
X 1 is —CH 2 —O—; and
R 40 is
23. The method of claim 1 wherein R 1 is —H, —OH, an aliphatic group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —COOH, —CN or —CO—NR 3 R 4 .
24. A method of treating a disease associated with aberrant leukocyte recruitment and/or activation mediated by chemokine receptor function, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:
or physiologically acceptable salt thereof, wherein:
n is an integer from one to four;
M is >NR 2 or >CR 1 R 2 ;
R 1 is —H, —OH, a halogen, an aliphatic group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR 3 R 4 , or R 1 is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;
R 2 is —OH, an acyl group, a substituted acyl group, —NR 5 R 6 , an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group;
R 3 , R 4 , R 5 and R 6 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or
R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;
said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl;
Z is represented by:
wherein:
X 1 is —O—, —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —O—CH 2 —, —CH 2 —O—, —NR c —CH 2 —, —CH 2 —NR c —, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NR c —CO— or —CO—NR c —;
R c is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group;
R 40 is Q-aliphatic group or Q-substituted aliphatic group; and
Q is —C(O)O—.
25. The method of claim 24 wherein R 40 is Q-aliphatic group and the aliphatic group is a C 2 -C 20 linear alkyl, alkenyl or alkynyl group, a C 3 -C 20 branched alkyl or alkenyl group, a C 4 -C 20 branched alkynyl group, a C 3 -C 20 cyclic alkyl or alkenyl group, or a C 9 -C 20 cyclic alkynyl group.
26. The method of claim 21 wherein R 40 is Q-substituted aliphatic group, and the substituted aliphatic group is a C 2 -C 20 linear alkyl, alkenyl or alkynyl group, a C 3 -C 20 branched alkyl or alkenyl group, a C 4 -C 20 branched alkynyl group, a C 3 -C 20 cyclic alkyl or alkenyl group, or a C 9 -C 20 cyclic alkynyl group, that is substituted with —OH, —NR 24 R 25 , —CONR 24 R 25 , —(O) u —(CH 2 ) t —C(O)O—R 20 or —(O) u —(CH 2 ) t —OC(O)—R 20 .
27. The method of claim 24 wherein R 1 is —H, —OH, an aliphatic group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —COOH, —CN or —CO—NR 3 R 4 .
28. The method of claim 24 wherein R 1 is —H or —OH and R 2 is an aromatic group or substituted aromatic group.
29. The method of claim 28 wherein X 1 is —CH—CH—or —CH—S—.
30. The method of claim 28 wherein X 1 is —CH—O—.
31. A method of treating a disease associated with aberrant leukocyte recruitment and/or activation mediated by chemokine receptor function, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:
or physiologically acceptable salt thereof, wherein:
n is an integer from one to four;
M is >CR 1 R 2 ;
R 1 is —N 3 , —NR 3 R 4 , an aminoalkyl group or a substituted aliphatic group;
R 2 is —OH, an acyl group, a substituted acyl group, —NR 5 R 6 , an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group);
R 3 , R 4 , R 5 and R 6 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or
R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;
said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl;
Z is represented by:
wherein:
X 1 is a bond, —O—, —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —O—CH 2 —, —CH 2 —O—, —NR c —CH 2 —, —CH 2 —NR c —, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NR c —CO— or —CO—NR c —;
R c is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and
Ring A and Ring B are independently substituted or unsubstituted.
32. The method of claim 30 wherein R 1 is —N 3 or —NR 3 R 4 .
33. The method of claim 30 wherein X 1 is —CH—CH—or —CH—S—.
34. The method of claim 30 wherein X 1 is —CH—O—.
35. The method of claim 30 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X 1 in ring C, and Z is represented by the structural formula:
wherein R 40 is —OH, —COOH, —NO 2 , halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR 24 R 25 , —CONR 24 R 25 , Q-(aliphatic group), Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 or —(O) u —(CH 2 ) t —NHC(O)O—R 20 ;
R 20 , R 21 or R 22 are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or
R 21 and R 22 , taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring;
Q is —NR 24 C(O)—, —NR 24 S(O) 2 — or —C(O)O—;
R 24 and R 25 are independently —H, —OH, an aliphatic group or a substituted aliphatic group;
u is zero or one; and
t is an integer from zero to 3; and
said electron withdrawing group is alkylimino, alkylsulfonyl, carboxamido, carboxylic alkyl ester, —CH═NH or —CN.
36. The method of claim 35 wherein R 40 is Q-aliphatic group or Q-substituted aliphatic group and Q is —C(O)O—.
37. The method of claim 36 wherein R 40 is Q-aliphatic group and the aliphatic group is a C 2 -C 20 linear alkyl, alkenyl or alkynyl group, a C 3 -C 20 branched alkyl or alkenyl group, a C 4 -C 20 branched alkynyl group, a C 3 -C 20 cyclic alkyl or alkenyl group, or a C 9 -C 20 cyclic alkynyl group.
38. The method of claim 36 wherein R 40 is Q-substituted aliphatic group, and the substituted aliphatic group is a C 2 -C 20 linear alkyl, alkenyl or alkynyl group, a C 3 -C 20 branched alkyl or alkenyl group, a C 4 -C 20 branched alkynyl group, a C 3 -C 20 cyclic alkyl or alkenyl group, or a C 9 -C 20 cyclic alkynyl group that is substituted with —OH, —NR 24 R 25 , —CONR 24 R 25 , —(O) u —(CH 2 ) t —C(O)O—R 20 or —(O) u —(CH 2 ) t —OC(O)—R 20 .
39. A method of treating a disease associated with aberrant leukocyte recruitment and/or activation mediated by chemokine receptor function, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:
or physiologically acceptable salt thereof, wherein:
n is an integer from one to four;
M is >NR 2 or >CR 1 R 2 ;
R 1 is —H, —OH, —N 3 , a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR 3 R 4 , —NR 3 R 4 or R 1 is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;
R 2 is —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group);
R 3 , R 4 , R 5 and R 6 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or
R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;
said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl;
Z is represented by:
wherein:
X 1 is a bond, —O—, —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —O—CH 2 —, —CH 2 —O—, —NR c —CH 2 —, —CH 2 —NR c —, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NR c —CO— or —CO—NR c —;
R c is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and
Ring A and Ring B are independently substituted or unsubstituted.
40. The method of claim 39 wherein X 1 is —CH—CH—or —CH—S—.
41. The method of claim 39 wherein X 1 is —CH—O—.
42. The method of claim 39 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X 1 in ring C, and Z is represented by the structural formula:
wherein R 40 is —OH, —COOH, —NO 2 , halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR 24 R 25 , —CONR 24 R 25 , Q-(aliphatic group), Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 or —(O) u —(CH 2 ) t —NHC(O)O—R 20 ;
R 20 , R 21 or R 22 are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or
R 21 and R 22 , taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring;
Q is —NR 24 C(O)—, —NR 24 S(O) 2 — or —C(O)O—;
R 24 and R 25 are independently —H, —OH, an aliphatic group or a substituted aliphatic group;
u is zero or one;
t is an integer from zero to 3; and
said electron withdrawing group is alkylimino, alkylsulfonyl, carboxamido, carboxylic alkyl ester, —CH═NH or —CN.
43. The method of claim 39 wherein R 40 is Q-aliphatic group or Q-substituted aliphatic group and Q is —C(O)O—.
44. The method of claim 43 wherein R 40 is Q-aliphatic group and the aliphatic group is a C 2 -C 20 linear alkyl, alkenyl or alkynyl group, a C 3 -C 20 branched alkyl or alkenyl group, a C 4 -C 20 branched alkynyl group, a C 3 -C 20 cyclic alkyl or alkenyl group, or a C 9 -C 20 cyclic alkynyl group.
45. The method of claim 43 wherein R 40 is Q-substituted aliphatic group, and the substituted aliphatic group is a C 2 -C 20 linear alkyl, alkenyl or alkynyl group, a C 3 -C 20 branched alkyl or alkenyl group, a C 4 -C 20 branched alkynyl group, a C 3 -C 20 cyclic alkyl or alkenyl group, or a C 9 -C 20 cyclic alkyl group that is substituted with —OH, —NR 24 R 25 , —CONR 24 R 25 , —(O) u —(CH 2 ) t —C(O)O—R 20 or —(O) u —(CH 2 ) t —OC(O)—R 20 .
46. The compound of claim 12 wherein R 1 is —H, —OH, an aliphatic group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —COOH, —CN or —CO—NR 3 R 4 .
47. A compound represented by the following structural formula:
or physiologically acceptable salt thereof, wherein:
n is an integer from one to four;
M is >NR 2 or >CR 1 R 2 ;
R 1 is —H, —OH, a halogen, an aliphatic group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR 3 R 4 , or R 1 is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;
R 2 is —OH, an acyl group, a substituted acyl group, —NR 5 R 6 , an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group;
R 3 , R 4 , R 5 and R 6 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or
R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;
said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl;
Z is represented by:
wherein:
X 1 is —O—, —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —O—CH 2 —, —CH 2 —O—, —NR c —CH 2 —, —CH 2 —NR c —, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NR c —CO— or —CO—NR c —;
R c is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group;
R 40 is Q-aliphatic group or Q-substituted aliphatic group; and
Q is —C(O)O—.
48. The compound of claim 46 wherein R 40 is Q-aliphatic group and the aliphatic group is a C 2 -C 20 linear alkyl, alkenyl or alkynyl group, a C 3 -C 20 branched alkyl or alkenyl group, a C 4 -C 20 branched alkynyl group, a C 3 -C 20 cyclic alkyl or alkenyl group, or a C 9 -C 20 cyclic alkynyl group.
49. The compound of claim 46 wherein R 40 is Q-substituted aliphatic group, and the substituted aliphatic group is a C 2 -C 20 linear alkyl, alkenyl or alkynyl group, a C 3 -C 20 branched alkyl or alkenyl group, a C 4 -C 20 branched alkynyl group, a C 3 -C 20 cyclic alkyl or alkenyl group, or a C 9 -C 20 cyclic alkynyl group, that is substituted with —OH, —NR 24 R 25 , —CONR 24 R 25 , —(O) u —(CH 2 ) t —C(O)O—R 20 or —(O) u —(CH 2 ) t —OC(O)—R 20 .
50. The compound of claim 47 wherein R 1 is —H, —OH, an aliphatic group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —COOH, —CN or —CO—NR 3 R 4 .
51. The compound of claim 47 wherein R 1 is —H or —OH and R 2 is an aromatic group or substituted aromatic group.
52. The compound of claim 51 wherein X 1 is —CH—CH—or —CH—S—.
53. The compound of claim 51 wherein X 1 is —CH—O—.
54. A compound represented by the following structural formula:
or physiologically acceptable salt thereof, wherein:
n is an integer from one to four;
M is >CR 1 R 2 ;
R 1 is —N 3 , —NR 3 R 4 , an aminoalkyl group or a substituted aliphatic group;
R 2 is —OH, an acyl group, a substituted acyl group, —NR 5 R 6 , an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group);
R 3 , R 4 , R 1 and R 6 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or
R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;
said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl;
Z is represented by:
wherein:
X 1 is a bond, —O—, —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —O—CH 2 —, —CH 2 —O—, —NR c —CH 2 —, —CH 2 —NR c —, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NR c —CO— or —CO—NR c —;
R c is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and
Ring A and Ring B are independently substituted or unsubstituted.
55. The compound of claim 54 wherein R 1 is —N 3 or —NR 3 R 4 .
56. The compound of claim 54 wherein X 1 is —CH—CH—or —CH—S—.
57. The compound of claim 54 wherein X 1 is —CH—O—.
58. The compound of claim 54 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X 1 in ring C, and Z is represented by the structural formula:
wherein R 40 is —OH, —COOH, —NO 2 , halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR 24 R 25 , —CONR 24 R 25 , Q-(aliphatic group), Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 or —(O) u —(CH 2 ) t —NHC(O)O—R 20 ;
R 20 , R 21 or R 22 are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or
R 21 and R 22 , taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring;
Q is —NR 24 C(O)—, —NR 24 S(O) 2 — or —C(O)O—;
R 24 and R 25 are independently —H, —OH, an aliphatic group or a substituted aliphatic group;
u is zero or one;
t is an integer from zero to 3; and
said electron withdrawing group is alkylimino, alkylsulfonyl, carboxamido, carboxylic alkyl ester, —CH═NH or —CN.
59. The compound of claim 58 wherein R 40 is Q-aliphatic group or Q-substituted aliphatic group and Q is —C(O)O—.
60. The compound of claim 59 wherein R 40 is Q-aliphatic group and the aliphatic group is a C 2 -C 20 linear alkyl, alkenyl or alkynyl group, a C 3 -C 20 branched alkyl or alkenyl group, a C 4 -C 20 branched alkynyl group, a C 3 -C 20 cyclic alkyl or alkenyl group, or a C 9 -C 20 cyclic alkynyl group.
61. The compound of claim 59 wherein R 40 is Q-substituted aliphatic group, and the substituted aliphatic group is a C 2 -C 20 linear alkyl, alkenyl or alkynyl group, a C 3 -C 20 branched alkyl or alkenyl group, a C 4 -C 20 branched alkynyl group, a C 3 -C 20 cyclic alkyl or alkenyl group, or a C 9 -C 20 cyclic alkynyl group, that is substituted with —OH, —NR 24 R 25 , —CONR 24 R 25 , —(O) u —(CH 2 ) t —C(O)O—R 20 or —(O) u —(CH 2 ) t —,OC(O)—R 20 .
62. A compound represented by the following structural formula:
or physiologically acceptable salt thereof, wherein:
n is an integer from one to four;
M is >NR 2 or >CR 1 R 2 ;
R 1 is —H, —OH, —N 3 , a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR 3 R 4 , —NR 3 R 4 or R 1 is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;
R 2 is —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group);
R 3 , R 4 , R 5 and R 6 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or
R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;
said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl;
Z is represented by:
wherein:
X 1 is a bond, —O—, —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —O—CH 2 —, —CH 2 —O—, —NR c —CH 2 —, —CH 2 —NR c —, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NR c —CO—or —CO—NR c —;
R c is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and
Ring A and Ring B are independently substituted or unsubstituted.
63. The compound of claim 62 wherein X 1 is —CH—CH—or —CH—S—.
64. The compound of claim 62 wherein X 1 is —CH—O—.
65. The compound of claim 62 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X 1 in ring C, and Z is represented by the structural formula:
wherein R 40 is —OH, —COOH, —NO 2 , halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR 24 R 25 , —CONR 24 R 25 , Q-(aliphatic group), Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 or —(O) u —(CH 2 ) t —NHC(O)O—R 20 ;
R 20 , R 21 or R 22 are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or
R 21 and R 22 , taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring;
Q is —NR 24 C(O)—, —NR 24 S(O) 2 — or —C(O)O—;
R 24 and R 25 are independently —H, —OH, an aliphatic group or a substituted aliphatic group;
u is zero or one;
t is an integer from zero to 3; and
said electron withdrawing group is alkylimino, alkylsulfonyl, carboxamido, carboxylic alkyl ester, —CH═NH or —CN.
66. The compound of claim 65 wherein R 40 is Q-aliphatic group or Q-substituted aliphatic group and Q is —C(O)O—.
67. The compound of claim 66 wherein R 40 is Q-aliphatic group and the aliphatic group is a C 2 -C 20 linear alkyl, alkenyl or alkynyl group, a C 3 -C 20 branched alkyl or alkenyl group, a C 4 -C 20 branched alkynyl group, a C 3 -C 20 cyclic alkyl or alkenyl group, or a C 9 -C 20 cyclic alkynyl group.
68. The compound of claim 66 wherein R 40 is Q-substituted aliphatic group, and the substituted aliphatic group is a C 2 -C 20 linear alkyl, alkenyl or alkynyl group, a C 3 -C 20 branched alkyl or alkenyl group, a C 4 -C 20 branched alkynyl group, a C 3 -C 20 cyclic alkyl or alkenyl group, or a C 9 -C 20 cyclic alkynyl group, that is substituted with —OH, —NR 24 R 25 , —CONR 24 R 25 , —(O) u —(CH 2 ) t —C(O)O—R 20 or —(O) u —(CH 2 ) t —OC(O)—R 20 .
69. A method of antagonizing a chemokine receptor in a mammal, comprising administering to a mammal in need thereof a chemokine receptor antagonizing amount of a compound represented by the following structural formula:
or physiologically acceptable salt thereof, wherein:
n is an integer from one to four;
M is >NR 2 or >CR 1 R 2 ;
R 1 is —H, —OH, a halogen, an aliphatic group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR 3 R 4 or R 1 is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;
R 2 is —OH, an acyl group, a substituted acyl group, —NR 5 R 6 , an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group;
R 3 , R 4 , R 1 and R 6 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or
R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;
said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl;
Z is represented by:
wherein:
X 1 is —O—, —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —O—CH 2 —, —CH 2 —O—, —NR c —CH 2 —, —CH 2 —NR c —, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NR c —CO—or —CO—NR c —;
R c is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group;
R 40 is —COOH, —NO 2 , a substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR 24 R 25 , —CONR 24 R 25 , Q-(aliphatic group), Q-(substituted aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), —(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 or —(O) u —(CH 2 ) t —NHC(O)O—R 20 ;
R 20 , R 21 or R 22 are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or
R 21 and R 22 taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring;
Q is —NR 24 C(O)—, —NR 24 S(O) 2 — or —C(O)O—;
R 24 and R 25 are independently —H, —OH, an aliphatic group or a substituted aliphatic group;
u is zero or one; and
t is an integer from zero to 3.
70. The method of claim 69 wherein R 1 is —H, —OH, an aliphatic group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —COOH, —CN or —CO—NR 3 R 4 .
71. The method of claim 69 wherein said mammal has a chronic inflammatory disorder.
72. The method of claim 69 wherein said mammal has a disease selected from the group consisting of arthritis, atherosclerosis, arteriosclerosis, restenosis, ischemia/reperfusion injury, psoriasis, multiple sclerosis, rejection of a transplanted organ or tissue, graft versus host disease, ulcerative colitis, Crohn's disease, allergy, asthma, AIDS associated encephalitis, AIDS related maculopapular skin eruption, AIDS related interstitial pneumonia, AIDS related enteropathy, AIDS related periportal hepatic inflammation and AIDS related glomerulonephritis.
73. The method of claim 69 wherein said mammal has a disease selected from the group consisting of arthritis, psoriasis, multiple sclerosis, rejection of a transplanted organ or tissue, graft versus host disease, ulcerative colitis, Crohn's disease, allergy, asthma, AIDS associated encephalitis, AIDS related maculopapular skin eruption, AIDS related interstitial pneumonia, AIDS related enteropathy, AIDS related periportal hepatic inflammation and AIDS related glomerulonephritis.
74. The method of claim 69 wherein said mammal has a disease selected from the group consisting of ulcerative colitis, Crohn's disease, arthritis, psoriasis, multiple sclerosis, allergy and asthma.
75. A method of antagonizing a chemokine receptor in a mammal, comprising administering to a mammal in need thereof a chemokine receptor antagonizing amount of a compound represented by the following structural formula:
or physiologically acceptable salt thereof, wherein:
n is an integer from one to four;
M is >CR 1 R 2 ;
R 1 is —N 3 , —NR 3 R 4 , an aminoalkyl group or a substituted aliphatic group;
R 2 is —OH, an acyl group, a substituted acyl group, —NR 5 R 6 , an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group);
R 3 , R 4 , R 5 and R 6 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or
R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;
said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl;
Z is represented by:
wherein:
X 1 is a bond, —O—, —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —O—CH 2 —, —CH 2 —O—, —NR c —CH 2 —, —CH 2 —NR c —, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NR c —CO—or —CO—NR c —;
R c is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and
Ring A and Ring B are independently substituted or unsubstituted.
76. The method of claim 75 wherein R 1 is —N 3 or —NR 3 R 4 .
77. The method of claim 75 wherein said mammal has a chronic inflammatory disorder.
78. The method of claim 75 wherein said mammal has a disease selected from the group consisting of arthritis, atherosclerosis, arteriosclerosis, restenosis, ischemia/reperfusion injury, psoriasis, multiple sclerosis, rejection of a transplanted organ or tissue, graft versus host disease, ulcerative colitis, Crohn's disease, allergy, asthma, AIDS associated encephalitis, AIDS related maculopapular skin eruption, AIDS related interstitial pneumonia, AIDS related enteropathy, AIDS related periportal hepatic inflammation and AIDS related glomerulonephritis.
79. The method of claim 75 wherein said mammal has a disease selected from the group consisting of ulcerative colitis, Crohn's disease, arthritis, psoriasis, multiple sclerosis, allergy and asthma.
80. A method of antagonizing a chemokine receptor in a mammal, comprising administering to a mammal in need thereof a chemokine receptor antagonizing amount of a compound represented by the following structural formula:
or physiologically acceptable salt thereof, wherein:
n is an integer from one to four;
M is >NR 2 or >CR 1 R 2 ;
R 1 is —H, —OH, —N 3 , a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR 3 R 4 , —NR 3 R 4 or R 1 is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;
R 2 is —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group);
R 3 , R 4 , R 5 and R 6 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or
R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;
said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl;
Z is represented by:
wherein:
X 1 is a bond, —O—, —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —O—CH 2 —, —CH 2 —O—, —NR c —CH 2 —, —CH 2 —NR c —, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NR c —CO—or —CO—NR c —;
R c is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and
Ring A and Ring B are independently substituted or unsubstituted.
81. The method of claim 80 wherein said mammal has a chronic inflammatory disorder.
82. The method of claim 80 wherein said mammal has a disease selected from the group consisting of arthritis, atherosclerosis, arteriosclerosis, restenosis, ischemia/reperfusion injury, psoriasis, multiple sclerosis, rejection of a transplanted organ or tissue, graft versus host disease, ulcerative colitis, Crohn's disease, allergy, asthma, AIDS associated encephalitis, AIDS related maculopapular skin eruption, AIDS related interstitial pneumonia, AIDS related enteropathy, AIDS related periportal hepatic inflammation and AIDS related glomerulonephritis.
83. The method of claim 80 wherein said mammal has a disease selected from the group consisting of ulcerative colitis, Crohn's disease, arthritis, psoriasis, multiple sclerosis, allergy and asthma.Cited by (0)
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